Changes in dopaminergic transmission in mesolimbic and mesocortical pathways have been implicated in certain psychiatric disorders and in the mechanism of action of antipsychotic drugs such as haloperidol. The functional activity of these dopaminergic neurons is most likely dependent on their pre- and/or postsynaptic relations with neurons containing other transmitters or modulators. The goals of the presently funded and proposed studies are to determine: (1) the anatomical substrate for functional interactions between the dopaminergic neurons and neurons containing gamma aminobutyric acid (GABA), substance P, or neurotensin, and (2) the time-dependent alterations In the ultrastructural features of neurons containing one or more of the identified transmitters following chronic treatment with neuroleptic drugs. These goals will be achieved by examining the single or dual immunocytochemical localization of tyrosine hydroxylase, an enzyme involved in catecholamine synthesis, GABA, substance P and neurotensin in the nucleus accumbens (Study 1), medial prefrontal cortex (Study 11), and ventral tegmental area (Study 111) of normal adult rats and rats receiving long-term (2-4 mo) treatment with haloperidol. In addition, the anatomical substrate for functional relationships between dopaminergic axons or GABAergic neurons and other afferents from the hippocampal formation or amygdaloid nuclei will be examined in the nucleus accumbens by combining immunoautoradiographic labeling with anterograde degeneration or transport of conjugated horseradish peroxidase. The results will be quantitatively examined by computer-assisted densitometry of immunoautoradiographs and morphometric analysis of peroxidase- labeled profiles by electron microscopy. Further characterization of normal synaptic relationships and morphological changes observed following chronic administration of a neuroleptic drug is relevant to the understanding of the etiology and the implementation of better treatments for psychiatric disorders which Involve mesolimbic and cortical dopaminergic neurons.
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